Identification of Nitric Oxide-Donating Ripasudil Derivatives with Intraocular Pressure Lowering and Retinal Ganglion Cell Protection Activities

Based on the synergistic therapeutic effect of nitric
oxide (NO)
and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a
new group of NO-donating ripasudil derivatives RNO-1–RNO-6 was designed, synthesized, and biologically evaluated.
The results demonstrated that the most active compound RNO-6 maintained potent ROCK inhibitory and NO releasing abilities, reversibly
depolymerized F-actin, and suppressed mitochondrial respiration in
human trabecular meshwork (HTM) cells. Topical administration of RNO-6 (0.26%) in chronic ocular hypertension glaucoma mice
exhibited significant IOP lowering and visual function and retinal
ganglion cell (RGC) protection activities, superior to an equal molar
dose of ripasudil. RNO-6 could be a promising agent for
glaucoma or ocular hypertension, warranting further investigation.